Androgen is synthesized in the testis and adrenal cortex, bound to an androgen receptor in a target organ, and shows various physiological activities. Chemically, any natural androgen belongs to C19 steroid. The major androgen is testosterone mainly synthesized in the testis, which shows strong uptake in a target cell and strong physiological activity. In female, adrenal cortex is a major androgen supply source.
Androgen is involved in the growth and function maintenance of genital organ (prostate, vesicular gland, epididymis, vas deferens and the like), sex differentiation in the embryonic stage, spermatozoon formation, expression of secondary sexual characteristics (induction of masculinization in, for example, muscle-skeleton, voice, fat distribution etc., and the like), promotion of protein elaboration in muscle and the like, bone metabolism and the like. Therefore, shortage of androgen due to testis dysfunction, castration and the like results in insufficient actions mentioned above, thus leading to various diseases and degraded QOL (quality of life). To deal with the situation, a treatment method to supplement androgen is generally employed. Besides testosterone, synthetic androgen showing different balance of androgen action has been studied and put to practical use in clinical situations.
On the other hand, when androgen is involved in the progression of pathology, a treatment to decrease androgen is employed. For example, in androgen dependent prostate cancer, castration and administration of GnRH agonist decrease testosterone and increase a treatment effect.
For supplementing androgen, testosterone and synthetic androgen are generally used. However, they have a steroid skeleton, which places much burden on the liver or shows other steroid hormone action. Therefore, an androgen receptor modulator (particularly agonist) having a non-steroidal skeleton is considered to be useful for the improvement of pathology caused by insufficient androgen action (hypogonadism, male climacteric disorder and the like) and pathology expected to show improvement by the action of androgen (osteoporosis and the like).
It is known that a naphthalene derivative having a pyrrolidine ring has a superior androgen receptor modulator action (patent reference 1). However, this reference does not disclose a pyrrolidinobenzene derivative having a substituent at the 3-position of pyrrolidine ring.
In addition, a benzene derivative having a pyrrolidine ring is known (patent references 2 and 3, non-patent references 1 to 5). However, a compound having a substituent at the 3-position of pyrrolidine ring is not disclosed.
Furthermore, a benzene derivative having a substituent at the 3-position of pyrrolidine ring is known (patent references 4 and 5, non-patent references 6 to 8). However, a description relating to an androgen receptor modulator action is not found.
[patent reference 1] WO 2004/16576
[patent reference 2] JP-A-2002-88073
[patent reference 3] WO 2000/00464
[patent reference 4] US 2004/0083559 B
[patent reference 5] WO 01/54726
[non-patent reference 1] Tetrahedron, 2002, vol. 58, No. 43, p. 8793-8798
[non-patent reference 2] Tetrahedron Letters, 2001, vol. 42, No. 40, p. 7127-7129
[non-patent reference 3] Chirality, 2000, vol. 12, No. 2, p. 63-70
[non-patent reference 4] Journal of Liquid Chromatography & Related Technologies, 2000, vol. 23, No. 8, p. 1203-1215
[non-patent reference 5] Justus Liebigs Annalen der Chemie, 1968, vol. 716, p. 47-60
[non-patent reference 6] Organic Letters, 2005, vol. 7, No. 13, p. 2575-2578
[non-patent reference 7] Journal of Medicinal Chemistry, 1972, vol. 15, p. 827
[non-patent reference 8] Journal of Chemical Society, 1961, p. 189